5-aroxymethyloxazolidines



United States Patent S-AROXYMETHYLOXAZOLIDINES Albert Frederick Crowther and Leslie Harold Smith, Macclesfield, England, assignors to Imperial Chemical Industries Limited, London, England, a corporation of Great Britain No Drawing. Filed June 18, 1964, Ser. No. 376,231 Claims priority, application Great Britain, July 19, 1963,

6 Claims. (Cl. 260-307) wherein Ar stands for a substituted, R stands for an alkyl, aralkyl radical, any of which may tuted, and R stands for hydrogen or an alkyl radical, and the salts thereof. Y

It is to beunderstood that the above definition of oxazolidine derivatives encompasses all possible stereoisomers thereof, and mixtures thereof. It is also to be understood that, in this specification, unqualified expressions in which there is no mention of substituents, for example alkyl radical or alkenyl radical, only encompass the unsubstituted radicals in question.

As a suitable value for R when it stands for an alkyl radical there may be mentioned, for example, an alkyl radical of not more than 10 carbon atoms, for example the isopropyl, s-butyl, t-butyl or 2-ethylhexyl radical. As a suitable value for R when it stands for a substituted alkyl radical there may be mentioned, for example, an alkyl radical of not more than 10 carbon atoms bearing one or more hydroxy radicals. As a suitable value for R when it stands for an aralkyl radical, optionally substituted, there may be mentioned, for example, an aralkyl radical of not more than 10 carbon atoms, optionally cycloalkyl, alkenyl or phenyl, naphthyl or 5,6,7,8-tetra- I hydro-l-naphthyl radical, any of which may optionally be optionally be substi t-butyl, t-amyl, trifluoromethyl, methoxy, ethoxy, n-butoxy, acetyl, benzoyl, phenyl, phenoxy, phenylthio or benzyl radical, and hydroxy, nitro and heterocyclic radicals, for example monocyclic and polycyclic heteroaromatic radicals containing one or more oxygen, nitrogen and/or sulphur atoms as hetero-atom(s), optionally substituted, for example such a radical comprising a 5- or 6-membered heteroaromatic ring, for example a 2-pyridyl, 2-indolyl, Z-benzoxazolyl or Z-benzthiazolyl radical, optionally substituted.

As suitable salts of the said oxazolidine derivatives there may be mentioned, for example, acid-addition salts, for example salts derived from inorganic acids, for example hydrochlorides, hydrobromides, phosphates or sulphates, or salts derived from organic acids, for example oxalates, lactates, tartrates, acetates, salicylates or citrates. As specific oxazolidine derivatives of the invention A there may be mentioned, for example, 3-isopropyl-5-(lnaphthoxymethyl)oxazolidine, 3 (l-methyl-3-phenylpropyl)-5-(3-tolyloxymethyl)oxazolidine and 3-s-butyl-5-(5, 6,7,8-tetrahydro-l-naphthoxymethyl)oxazolidine, and the salts thereof.

According to a further feature of the invention we provide a process for the manufacture of the oxazolidine derivatives of the invention which comprises the interaction of an alkanolamine derivative of the formula:

substituted with, for example, one or more hydroxy, alkyl 7 when it stands fora substituted alkyl radical oran aralkyl radical are, for example, the 2-hydroxy-1,l-dimethylethyl,

benzyl or 1-methyl-3 phenylpropy1 radical. As a suitable value for R when it stands for a cycloalkyl radical there may be mentioned, for example, a cycloalkyl radical of not more than 10 carbonatoms, for example the cyclohexyl radical. As a suitable value for R when it stands for an alkenyl radical, optionally substituted, there may be mentioned, for example, an alkenyl radical of not more than 10 carbon atoms, for'example the allyl radical.

As a suitable value for R when it stands for an alkyl radical there may be mentioned, for example, an alkyl radical of not more than 10 carbon atoms, for example the isopropyl radical.

As suitable substituents which may optionally be pres- 10 carbon atoms, for example the methyl, ethyl, isopro'pyl,"

. or iodine, and it may ArO.CH .CHOH.CH .NHR

wherein Ar and R have the meanings stated above, or a salt thereof, with an aldehyde of the formula R .CHO where R has the meaning stated above.

The interaction may be carried out in a diluent or solvent, for example ethanol, optionally in the presence of a catalyst, for example hydrochloric acid, acetic acid be accelerated or completed by the application of heat. The water formed during the reaction may be removed by azeotropic distillation using a suitable solvent, for example benzene, toluene or chloroform, as an entraining agent, or it may be removed by means of a dehydrating agent, for example anhydrous potassium carbonate.

The oxazolidine derivatives of the invention possess 8- adrenergic blocking activity and they are therefore useful in the treatment or prophylaxis of heart diseases such as cardiac arrhythmias and angina pectoris.

According to a further feature of the invention, therefore, we provide pharmaceutical compositions comprising one or more oxazolidine derivatives of the formula:

wherein Ar, R and R have the meanings stated above, or a salt thereof, in admixture with a pharmaceuticallyacceptable diluent or carrier.

The pharmaceutical compositions may be, for example, in the form of tablets, capsules, aqueous or oily solutions, aqueous or oily suspensions, dispersible powders, syrups or elixirs, and may be obtained by conventional means.

The invention is illustrated but not limited by the following examples in which the parts are by weight:

Example I A mixture of 2.6 parts of 1-isopropylamino-3-(l-naphthoxy)-2-propanol, 1 part of a 40% aqueous solution of formaldehyde and 16 parts of ethanol is heated under reflux for 3 hours. A further 1 part of 40% aqueous formaldehyde is then added and the mixture is heated under reflux for a further 16 hours. The solution is then evaporated to dryness in vacuo to leave a residue which is Patented May 2, 1967' The process descri that the 1 isoprop Example 2 used as starting material is rep starting material and there are t ing compounds:

bed in Example 1 is repeated except ylarnino-3-(1-naphth0xy)-2-propanol laced by the appropriate hus obtained the follow- Example 5 lting mixture is filtered. her and then dried. of n-propanol A mixture of 2.6 parts of 1-isopropylamino-3-(1- naphthoxy)-2-propanol, 1.4 parts of isobutyraldehyde and 40 parts of benzene is heated under reflux for 16 hours, the water liberated in the course of the reaction being continuously removed by means of a Dean and Starke apparatus. The resulting solution is evaporated under reduced pressure, and the residue is dissolved in warm light petroleum (B.P. 80100 C.). The solution is cooled and filtered, and the filtrate is evaporated under reduced pressure. The residue is dissolved in ether, and ethereal hydrogen chloride is added. The resulting mixture is filtered, and the solid residue is washed with ether,

0 dried, and crystallised from a mixture of ethyl acetate 0H, and propanol. There 15 thus obtained 2,3-d1-1sopropyl- S-(I-naphthyloxymethyl)oxazolidine hydrochloride, M.P. 144146 C.

Substituent Crystallisation R in naphthalene Salt M.P. C.) solvent(s) nucleus Isopropyl 4-ruethyl Hydroehloride 159-160 Etlggl acletatel e 5110 Allyl Oxalate 168-170 Ethanol. 2-l1ydroxy-1,1-di- Picrate 166-168 n-Propanol.

methyl-ethyl.

Example 3 Example 6 used as starting material is rep ing compounds:

(1-naphthoxy)-2-propanol laced y the appropriate nitol is passed through a -mesh screen.

starting material and there are thus obtained the follow- A mixture of 10 parts of 3-isopropyl-S-(l-naphthoxymethyl)oxazolidine hydrochloride and parts of man- Sufficient of a 10% aqueous solution of gelatin is then added to make a stiff paste. The paste is passed through a 16-mesh screen, dried and then passed through a 20-mesh screen. To the resulting granules are added 6 parts of alginic 40 acid and 2 parts of magnesium stearate. The resulting 0H: mixture is compressed into tablets by known means. There are thus obtained tablets suitable for therapeutic purposes.

R1 Salt M.I. C.) Crystallisation solvent(s) s-Butyl Hydrochloride 107-109 Ethyl acetate. 2-ethy1hexyl x ate 180 Ethanol. Benzyl Hydroehloride 161-162 Ethyl acetate. Cyclohexyl do 142-143 Ethyl acetate/ethanol.

Example 4 What we claim is:

The process described in Exam lowing compounds:

ArO.CHa.OH-CH2 ple 1 is repeated except -naphthoxy) 2-propanol 5 5 laced by the appropriate starting material and there are thus obtained the fol- 1. A compound selected from the group consisting of oxazolidine derivatives of the formula:

ArO.CEz.CH-CH1 o N-R NR 60 wherein: Ar is selected from the group consisting of CH: phenyl, naphthyl, 5,6,7,8-tetrahydro-l-naphthyl, and said R Ar Salt M.P. C.) crystallisation s0lvent(s) Isopropy 3-brornophenyl Oxalate 153-154 Ethanol. Isopropyl... 3-methoxyphenyl. do 98-100 Ethyl acetate. Allyl 3,5-dimethyl- Hydro- 146 Ethyl acetate/ phenyl. chloride ethanol. l-methyl-B- 3-methylphenyl .do -121 Ethyl acetate.

phenylpropyl. Isopropyl Penltachloro- Oxalate 218-219 Aqueous ethanol.

p BUY 2-hydroxy-1, l-di- 2-phenoxy- Hydro- 2-ethoxyethanol/ methyl ethyl. phenyl. chloride. ether.

alkenyl of not more than 10' carbon atoms, alkoxy of 3 (1 not more than carbon atoms, acyl selected from the group consisting of acetyl and benzoyl, aryl of not more than 10 carbon atoms, aryloxy of not more than 10* carbon atoms, arylthio of not more than 10 carbon atoms, and aralkyl of not more than 10 carbon atoms, and R is selected from the group consisting of alkyl of not more than 10 carbon atoms, hydroxyalkyl of not more than 10 carbon atoms, cycloalkyl of not more than 10 carbon atoms, alkenyl of not more than 10 carbon atoms, and aralkyl of not more than 10 carbon atoms; and R is selected from the group consisting of hydrogen and alkyl of not more than 10 carbon atoms; and the pharmaceutically-acceptable acid-addition salts thereof.

2. A compound as claimed in claim 1 wherein Ar is phenyl containing at least one substituent selected from the group consisting of halogen, methyl, ethyl, isopropyl, t-butyl, t-amyl, methoxy, ethoxy, n-butoxy, acetyl, benzoyl, phenoxy, phenylthio, and benzyl.

3. A compound as claimed in claim 1 wherein R 4. A compound selected from the group consisting of 3-isopropyl-5-(1 naphthoxymethyl)oxazolidine and the pharmaceutically-acceptable acid-addition salts thereof.

5. A compound selected from the methyl methyl)-oxazolidine and the group consisting of 3 phenylpropyl) 5 (3 tolyloxypharmaceutically-acceptable acid-addition salts thereof.

6. A compound selected from the group consisting of 3 s butyl 5 (5,6,7,8

- tetrahydro l naphthoxy- 10 methy1)-oxazolidine and the pharmaceutically-acceptable acid-addition salts thereof.

stands for the Z-hydroxy-l,l-dimethylethyl, benzyl or 1- methyl-3-phenylpropyl radical,

References Cited by the Examiner UNITED STATES PATENTS 6/1959 Marsh et a1 l6765 7/1959 Marsh 1 67-65 112/1960 Zenitz 260- 7 12/ 19 64 Hodge 260307 FOREIGN PATENTS 8/ 1961 Netherlands. 

1. A COMPOUND SELECTED FROM THE GROUP CONSITING OF OXAZOLIDINE DERIVATIVES OF THE FORMULA: 